Project Summary In order to map large-scale brain activity and understand and treat neurological disorders, there is a common need for biomedical tools that can monitor and modulate neural activity. Despite many other alternatives, the electrophysiology which directly records the on-going electrical activity in circuit elements remains a powerful tool for investigating the neural function and dysfunction. The long term goal of this project is to develop a lifetime-stable, scalable, multifunctional, and magnetic resonance imaging-compatible neuron-electrode interface that enables high-fidelity recordings and high-precision stimulation. The central approach is to employ an entirely novel technique established on ensheathing axons within ?Channels (channels with micrometer dimensions) that enclose printed electrodes. The main hypothesis is that the axons growing through micron- scale channels can spontaneously form an electrical seal that isolates the axonal membrane patches to yield high signal-to-noise ratio (SNR) recording and immunity to mechanical vibrations or gliotic encapsulation of the electrodes. The rationale of this study is based on preliminary studies, in which during an action potential, the transmembrane current of ion-channels in the axonal membrane (patched inside the ?Channel) is forced to go through the axial resistive path of the ?Channel. The in-channel growth of axons increases this resistance and enhances the SNR per Ohm's law. Thus, contrary to the case for conventional electrodes, any additional resistance increase due to gliotic coverage should not reduce SNR, but instead enhance it. The design also should provide chronically-stable recordings from the same units for several years to life-time, since axons trapped in the ?Channel are likely to be immune to either mechanical vibration or gliosis. The immediate objective is to identify ?Channel geometries and soluble cues that promote axonal growth inside the ?Channel to maintain a robust ionic seal, which requires the development of novel high-throughput screening modalities. To that end, we will specifically (i) employ microfabrication techniques to create a library of ?Channel geometries and incorporate nanoporous electrodes that are capable of high fidelity recordings and in situ release of neurotropic factors; (ii) screen for optical ?Channel geometries and soluble factors in combination with an in vitro cortical neuron-astrocyte coculture model to ensure axonal growth into the channels and a spontaneous seal; and (iii) evaluate the performance of a prototype device that displays the successful geometries using an organotypic brain slice model. The expected outcome of the project is a novel class of neural devices that are scalable for large-scale monitoring and modulation of brain activity in animal models and human subjects.